WO2024078436A1 - Heterocyclic pyrimidine compound, pharmaceutical composition and application thereof - Google Patents

Abstract

The present disclosure discloses a compound having formula (I) or a pharmaceutically acceptable salt thereof which acts as a USP1 inhibitor, a pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof, and a use thereof in the prevention or treatment of diseases mediated by USP1.

Description

Heterocyclic pyrimidine compounds, pharmaceutical compositions and applications thereof

This disclosure claims the priority of the prior application filed with the State Intellectual Property Office of China on October 9, 2022, with patent application number 202211229728.2 and invention name “Heterocyclic pyrimidine compounds, pharmaceutical compositions and their applications”. The full text of the above-mentioned prior application is incorporated into this disclosure by reference.

Technical Field

The present disclosure belongs to the field of medical technology, and relates to a class of heterocyclic pyrimidine compounds, or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them, and uses thereof as ubiquitin-specific protease 1 (USP1) inhibitors in preventing or treating diseases associated with USP1.

Background technique

Ubiquitination is a reversible process involving a family of deubiquitinating enzymes (DUBs) that regulate a variety of cellular processes by deubiquitinating substrates. DUBs are encoded by approximately 100 human genes and are classified into six families, the largest of which is the ubiquitin-specific proteases (USPs) with more than 50 members. DUBs and their substrate proteins are frequently dysregulated in cancer, a phenomenon that supports the hypothesis that targeting specific DUB enzymes can enhance the ubiquitination and degradation of oncogenic substrates and regulate the activity of other key proteins involved in tumor growth, survival, differentiation, and maintenance of the tumor microenvironment (Hussain, S., et.al., "DUBs and cancer: The role of deubiquitinating enzymes as oncogenes, non-oncogenes and tumor suppressors." Cell Cycle 8, 1688-1697 (2009)).

Ubiquitin-specific protease 1 (USP1) is a cysteine isopeptidase of the USP subfamily in DUBs. The full-length human USP1 consists of 785 amino acids, including a catalytic triad consisting of Cys90, His593 and Asp751 (Nijman, S.M.B., et al. "The deubiquitinating enzyme USP1 regulates the fanconi anemia pathway." Mol. Cell 17, 331-339 (2005)). USP1 plays a role in DNA damage repair. USP1 itself is relatively inactive, and only when it combines with the auxiliary factor UAF1 to form a complex required for deubiquitinase activity can it obtain full enzyme activity. The USP1/UAF1 complex deubiquitinates monoubiquitinated PCNA (proliferating cell nuclear antigen) and monoubiquitinated FANCD2 (Fanconi anemia complementation group D2), two proteins that play important roles in the trans-translational synthesis (TLS) and Fanconi anemia (FA) pathways, respectively. Both pathways are required for the repair of DNA damage caused by DNA cross-linking agents such as cisplatin and mitomycin C (MMC). The USP1/UAF1 complex also deubiquitinates FANCI (Fanconi anemia complementation group I). The significance of these findings was further confirmed by experiments showing that mice lacking USP1 are highly sensitive to DNA damage. Interestingly, the expression of USP1 is significantly increased in many cancers. Blocking USP1 to inhibit DNA repair can induce apoptosis in multiple myeloma cells and also enhance the sensitivity of lung cancer cells to cisplatin. These suggest that USP1 is a promising target for chemotherapy of certain cancers.

In summary, targeted inhibition of USP1 protein is a potential approach to prevent or treat cancer and other diseases. Therefore, the development of small molecule inhibitors of USP1 is necessary.

Summary of the invention

In one aspect, the present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

in,

Selected from the following structures:

R ^3a , R ^3b , R ⁴ , R ^5a , R ^5b are each independently selected from H, halogen, CN, OH, NH ₂ , -C(O)OR ^x , -C(O)R ^x , -NHC(O)R ^x , -OC ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl or 4-10 membered heterocyclyl, and the NH ₂ , -OC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl or 4-10 membered heterocyclyl is optionally substituted with R ^x ;

or R ^3a , R ^3b and the carbon atom to which they are attached together form a C ₃ -C ₁₀ cycloalkyl group or a 4-10 membered heterocyclic group, and the C ₃ -C ₁₀ cycloalkyl group or the 4-10 membered heterocyclic group is optionally substituted by R ^x ;

or R ^5a , R ^5b and the carbon atom to which they are attached together form a C ₃ -C ₁₀ cycloalkyl group or a 4-10 membered heterocyclic group, and the C ₃ -C ₁₀ cycloalkyl group or the 4-10 membered heterocyclic group is optionally substituted by R ^x ;

Ring A is selected from C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl, and the C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl is optionally substituted by ^Ra ;

Ring B is selected from C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, C ₄ -C ₁₀ cycloalkenyl or C ₃ -C ₁₀ cycloalkyl, wherein the C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, C ₄ -C ₁₀ cycloalkenyl or C ₃ -C ₁₀ cycloalkyl is optionally substituted with R ^b ;

Ring C is selected from C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl is optionally substituted by R ^c ;

Each of ^Ra , ^Rb , and ^Rc is independently selected from halogen, CN, OH, _NH2 , -C(O) ^ORx , -C(O) ^Rx , _C1 - _C6 alkyl, _-OC1 - _C6 alkyl, _C3 - _C10 cycloalkyl, or 4-10 membered heterocyclyl, wherein the _NH2 , _C1 - _C6 alkyl, -OC1- _C6 alkyl, _C3 - _C10 cycloalkyl, or _4-10 membered heterocyclyl is optionally substituted by ^Rx ;

Alternatively, R ^b , R ^c and the atoms to which they are attached together form a C ₄ -C ₁₀ cycloalkenyl group or a 4-10 membered heterocyclic group, and the C ₄ -C ₁₀ cycloalkenyl group or the 4-10 membered heterocyclic group is optionally substituted by R ^x ;

R ¹ and R ² are independently selected from H, halogen, CN, OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl or 4-10 membered heterocyclyl, wherein the OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl or 4-10 membered heterocyclyl is optionally substituted by R ^x ;

Alternatively, R ¹ , R ² and the atoms to which they are attached together form a C ₃ -C ₁₀ cycloalkyl group or a 4-7 membered heterocyclic group, and the C ₃ -C ₁₀ cycloalkyl group or the 4-7 membered heterocyclic group is optionally substituted by R ^x ;

^Rx is selected from halogen, CN, OH, _NH2 or _C1 - _C6 alkyl, wherein the OH, _NH2 or _C1 - _C6 alkyl is optionally substituted by _C1 - _C6 alkyl, _C3 - _C10 cycloalkyl or 4-7 membered heterocyclyl;

The condition is that when Selected from when R ^5a is selected from halogen, CN, OH, NH ₂ , -C(O)OR ^x , -C(O)R ^x , -OC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl or 4-9 membered heterocyclyl, and the NH ₂ , -OC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl or 4-9 membered heterocyclyl is optionally substituted by R ^x ;

Alternatively, R ^5a , R ^5b and the carbon atom to which they are attached form a C ₄ -C ₁₀ cycloalkyl group or a 4-9 membered heterocyclic group, and the C ₄ -C ₁₀ cycloalkyl group or the 4-9 membered heterocyclic group is optionally substituted by R ^x .

In some embodiments, R ^3a , R ^3b , R ⁴ , R ^5a , R ^5b are independently selected from H, —C(O)OR ^x , —C(O)R ^x , —OC ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, or 4-10 membered heterocyclyl, wherein the —OC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, or 4-10 membered heterocyclyl is optionally substituted with R ^x .

In some embodiments, R ^3a , R ^3b , R ⁴ , R ^5a , R ^5b are independently selected from H, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ alkyl, or C ₃ -C ₁₀ cycloalkyl, and the C ₁ -C ₆ alkyl or C ₃ -C ₁₀ cycloalkyl is optionally substituted with R ^x .

In some embodiments, R ^3a , R ^3b , R ⁴ , R ^5a , R ^5b are independently selected from H, CH ₃ , CD ₃ or cyclopropyl.

In some embodiments, R ^3a , R ^3b are independently selected from H, C ₁ -C ₆ deuterated alkyl, or C ₁ -C ₆ alkyl, said C ₁ -C ₆ alkyl being optionally substituted with R ^x .

In some embodiments _, R ⁴ is selected from H or C _{1 -C 6} alkyl, which is optionally substituted with R ^x .

In some embodiments, R ^5a is selected from halogen, CN, OH, NH ₂ , -C(O)OR ^x , -C(O)R ^x , -OC ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, or 4-9 membered heterocyclyl, and the NH ₂ , -OC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, or 4-9 membered heterocyclyl is optionally substituted with R ^x .

In some embodiments, R ^5a is selected from C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ alkyl, or C ₃ -C ₁₀ cycloalkyl, and the C ₁ -C ₆ alkyl or C ₃ -C ₁₀ cycloalkyl is optionally substituted with R ^x .

In some embodiments, R ^5b is selected from H or C _{1 -C 6} alkyl, _which is optionally substituted with R ^x .

In some embodiments, R ^5a , R ^5b and the carbon atom to which they are attached form a C ₃ -C ₁₀ cycloalkyl group, and the C ₃ -C ₁₀ cycloalkyl group is optionally substituted with R ^x .

In some embodiments, R ^5a , R ^5b and the carbon atom to which they are attached form a C ₄ -C ₁₀ cycloalkyl group, and the C ₄ -C ₁₀ cycloalkyl group is optionally substituted with R ^x .

In some embodiments, R ^5a , R ^5b and the carbon atom to which they are attached form a C ₄ -C ₆ cycloalkyl group, and the C ₄ -C ₆ cycloalkyl group is optionally substituted with R ^x .

In some embodiments, R ^5a , R ^5b and the carbon atom to which they are attached form a cyclobutyl group, which is optionally substituted with R ^x .

In some embodiments, Selected from the following structures:

In some embodiments, Selected from the following structures:

In some embodiments, Ring A is selected from 5-10 membered heteroaryl, which is optionally substituted with ^Ra .

In some embodiments, Ring A is selected from 5-6 membered heteroaryl, which is optionally substituted with ^Ra .

In some embodiments, Ring A is selected from pyrimidinyl, which is optionally substituted with ^Ra .

In some embodiments, Ring B is selected from C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl, wherein the C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl is optionally substituted with R ^b .

In some embodiments, Ring B is selected _from C _{6 -C 10} aryl, which is optionally substituted with R ^b .

In some embodiments, Ring B is selected from phenyl, which is optionally substituted with R ^b .

In some embodiments, Ring B is selected from phenyl.

In some embodiments, Ring C is selected from 5-10 membered heteroaryl or 4-10 membered heterocyclyl, which is optionally substituted with R ^c .

In some embodiments, Ring C is selected from 5-6 membered heteroaryl or 4-8 membered heterocyclyl, wherein the 5-6 membered heteroaryl or 4-8 membered heterocyclyl is optionally substituted with R ^c .

In some embodiments, ring C is selected from pyrazolyl, imidazolyl or The pyrazolyl, imidazolyl or Optionally substituted with R ^c .

In some embodiments, each of ^Ra , ^Rb , and ^Rc is independently selected from halogen, _C1 - _C6 alkyl, _-OC1 - _C6 alkyl, _C3- C ₁₀ cycloalkyl or 4-10 membered heterocyclyl, wherein the C ₁ -C ₆ alkyl, -OC ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl or 4-10 membered heterocyclyl is optionally substituted by R ^x .

In some embodiments, each ^Ra , ^Rb , ^Rc is independently selected from halogen, _C1 - _C6 alkyl, _-OC1 - _C6 alkyl, _C3 - _C6 cycloalkyl or 4-6 membered heterocyclyl, and the _C1 - _C6 alkyl, _-OC1 - _C6 alkyl, _C3 - _C6 cycloalkyl or 4-6 membered heterocyclyl is optionally substituted with ^Rx .

In some embodiments, each ^Ra , ^Rb , ^Rc is independently selected from _C1 - _C6 alkyl, _-OC1 - _C6 alkyl, _C3 - _C6 cycloalkyl, or 4-6 membered heterocyclyl, and the _C1 - _C6 alkyl, _-OC1 - _C6 alkyl, _C3 - _C6 cycloalkyl, or 4-6 membered heterocyclyl is optionally substituted with ^Rx .

In some embodiments, each ^Ra , ^Rb , ^Rc is independently selected from _CH3 , CH( _CH3 ) ₂ , -O- _CH3 , cyclopropyl, oxetanyl, or tetrahydropyrrolyl, said _CH3 , CH( _CH3 ) ₂ , -O- _CH3 , cyclopropyl, oxetanyl, or tetrahydropyrrolyl being optionally substituted with ^Rx .

In some embodiments, each ^Ra , ^Rb , ^Rc is independently selected from _CH3 , CH( _CH3 ) ₂ , _CF3 , -O- _CH3 , -O- _CHF2 , cyclopropyl, oxetanyl, or

In some embodiments, each ^Ra is independently selected from _-OC1 - _C6 alkyl or _C3 - _C10 cycloalkyl, said _-OC1 - _C6 alkyl or _{C3-C10 cycloalkyl} being optionally substituted with ^Rx .

In some embodiments, each ^Ra is independently selected from -O- _CH3 or cyclopropyl, which -O- _CH3 or cyclopropyl is optionally substituted with ^Rx .

In some embodiments, each Ra ^is independently selected from -O- _CH3 , -O- _CHF2 , or cyclopropyl.

In some embodiments, each R ^c is independently selected from C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, or 4-10 membered heterocyclyl, and the C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, or 4-10 membered heterocyclyl is optionally substituted with R ^x .

In some embodiments, each R ^c is independently selected from CH ₃ , CH(CH ₃ ) ₂ , cyclopropyl, oxetanyl, or tetrahydropyrrolyl, said CH ₃ , CH(CH ₃ ) ₂ , cyclopropyl, oxetanyl, or tetrahydropyrrolyl being optionally substituted with R ^x .

In some embodiments, each R ^c is independently selected from CH ₃ , CH(CH ₃ ) ₂ , CF ₃ , cyclopropyl, oxetanyl, or

In some embodiments, R ^b , R ^c , and the atoms to which they are attached together form a 4-10 membered heterocyclyl, which is optionally substituted with R ^x .

In some embodiments, R ¹ and R ² are independently selected from H, halogen, C ₁ -C ₆ alkyl or C ₃ -C ₁₀ cycloalkyl, and the C ₁ -C ₆ alkyl or C ₃ -C ₁₀ cycloalkyl is optionally substituted with R ^x .

In some embodiments, R ¹ and R ² are both H.

In some embodiments, R ^x is selected from halogen, NH ₂ or C ₁ -C ₆ alkyl, said NH ₂ or C ₁ -C ₆ alkyl optionally substituted with C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl or 4-7 membered heterocyclyl.

In some embodiments, R ^x is selected from halogen or C ₁ -C ₆ alkyl.

In some embodiments, R ^x is selected from F or CH ₃ .

The present disclosure also provides a compound selected from the following or a pharmaceutically acceptable salt thereof:

In another aspect, the present disclosure provides a pharmaceutical composition comprising the compound of formula (I) or the above-mentioned compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

In another aspect, the present disclosure provides a method for treating a disease mediated by USP1 in a mammal, comprising administering a therapeutically effective amount of formula (I) or the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.

In another aspect, the present disclosure provides use of formula (I) or the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for preventing or treating a disease mediated by USP1.

In another aspect, the present disclosure provides use of formula (I) or the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preventing or treating a disease mediated by USP1.

In another aspect, the present disclosure provides formula (I) or the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating a disease mediated by USP1.

In some embodiments, the USP1-mediated disease is a tumor.

In some embodiments, the tumor is, for example, a solid tumor, an adenocarcinoma, or a hematological tumor.

Any embodiment of any aspect of the present invention may be combined with other embodiments without contradiction . In addition, any technical feature in any embodiment of any aspect of the present invention may be applicable to the technical feature in other embodiments without contradiction.

Unless otherwise specified, the terms used in this disclosure have the following meanings, and the groups and term definitions recorded in this disclosure, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., can be arbitrarily combined and combined with each other. A specific term should not be considered uncertain or unclear in the absence of a special definition, but should be understood according to the common meaning in the art. When a trade name appears in this article, it is intended to refer to its corresponding commodity or its active ingredient.

In this article Indicates the connection site.

The graphic representations of racemates or enantiomerically pure compounds herein are from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, the wedge and dashed wedge keys are used. To indicate the absolute configuration of a stereocenter, use black real and imaginary bonds. Indicates the relative configuration of a stereocenter (such as the cis-trans configuration of an alicyclic compound).

The term "tautomer" refers to functional group isomers resulting from the rapid movement of an atom in two positions in a molecule. The compounds of the present disclosure may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Tautomers generally exist in equilibrium, and attempts to separate a single tautomer usually produce a mixture whose physical and chemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical characteristics within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; while in phenols, the enol form predominates. The present disclosure includes all tautomeric forms of the compounds.

The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.

The compounds of the present disclosure may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, and thus the compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. Specific geometric or stereoisomeric forms may be cis and trans isomers, E and Z geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, non- Enantiomers, (D)-isomers, (L)-isomers, and racemic mixtures or other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the definition of the compounds of the present invention. Substituents such as alkyl groups may contain additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms, and all of which are involved in the substituents and their mixtures are also within the definition of the compounds of the present invention. The compounds of the present invention containing asymmetric atoms can be isolated in optically pure form or in racemic form, and the optically pure form can be resolved from the racemic mixture or synthesized by using chiral raw materials or chiral reagents.

The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is an oxo (i.e., =O), it means that two hydrogen atoms are replaced, and the oxo will not occur on an aromatic group.

The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes both the occurrence and non-occurrence of the event or circumstance. For example, an ethyl group is "optionally" substituted with a halogen, which means that the ethyl group may be unsubstituted (CH ₂ CH ₃ ), monosubstituted (CH ₂ CH ₂ F, CH ₂ CH ₂ Cl, etc.), polysubstituted (CHFCH ₂ F, CH ₂ CHF ₂ , CHFCH ₂ Cl, CH ₂ CHCl ₂ , etc.) or fully substituted (CF ₂ CF ₃ , CF ₂ CCl ₃ , CCl ₂ CCl ₃ , etc.). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and/or cannot be synthesized will be introduced.

When any variable (eg, ^Ra , ^Rb ) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. For example, if a group is substituted with 2 ^Rb , each ^Rb has an independent option.

When the linking group mentioned in this article does not specify its connection direction, its connection direction is arbitrary. When L ¹ is selected from "C ₁ -C ₃ alkylene-O", L ¹ can connect ring Q and R ¹ from left to right to form "ring QC ₁ -C ₃ alkylene-OR ¹ ", or connect ring Q and R ¹ from right to left to form "ring QOC ₁ -C ₃ alkylene-R ¹ ".

When a substituent's bond crosses two atoms in a ring, the substituent may be bonded to any atom in the ring. It means that R ⁵ can be substituted at any position on the benzene ring.

_Cm - _Cn herein refers to an integer number of carbon atoms in the range of mn. For example, " _C1 - _C10 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.

The term "alkyl" refers to a hydrocarbon group of the general _{formula CnH2n +1} , which may be linear or branched. The term " _C1 - _C10 alkyl" is understood to mean a linear or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of the alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc.; the term "C 1 -C 1 -C 1 -C 1 -C 1 -C ₁ -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C The term "C 1 -C ₃ alkyl" may be understood to mean an alkyl group having 1 to 6 carbon atoms, and specific examples include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, and the like. The term "C ₁ -C ₃ alkyl" may be understood to mean a straight or branched saturated alkyl group having 1 to 3 carbon atoms. The "C ₁ -C ₁₀ alkyl" may include a range such as "C ₁ -C ₆ alkyl" or "C ₁ -C ₃ alkyl", and the "C ₁ -C ₆ alkyl" may further include a "C ₁ -C ₃ alkyl".

The term "deuterated alkyl" means that hydrogen on an alkyl group is replaced by deuterium, including monodeuterated alkyl and polydeuterated alkyl. For example, the term "C _1-6 deuterated alkyl" means C _1-6 alkyl as defined above substituted by one or more deuterium, including but not limited to CD ₃ , CH ₂ CD ₃ and the like.

The term "alkenyl" refers to an unsaturated fatty acid group consisting of a straight or branched chain of carbon and hydrogen atoms and having at least one double bond. Aliphatic hydrocarbon group. The term "C ₂ -C ₁₀ alkenyl" is understood to mean a straight or branched unsaturated hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, "C ₂ -C ₁₀ alkenyl" is preferably "C ₂ -C ₆ alkenyl", further preferably "C ₂ -C ₄ alkenyl", and further preferably C ₂ or C ₃ alkenyl. It is understood that in the case where the alkenyl contains more than one double bond, the double bonds may be separated or conjugated with each other. Specific examples of the alkenyl group include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl or (Z)-1-methylprop-1-enyl, etc.

The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one triple bond. The term "C ₂ -C ₁₀ alkynyl" may be understood to mean a straight or branched unsaturated hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Examples of "C ₂ -C ₁₀ alkynyl" include, but are not limited to, ethynyl (-C≡CH), propynyl (-C≡CCH _3, -CH ₂ C≡CH), but-1-ynyl, but-2-ynyl or but-3-ynyl. "C ₂ -C ₁₀ alkynyl" may include "C ₂ -C ₃ alkynyl", examples of "C ₂ -C ₃ alkynyl" include ethynyl (-C≡CH), prop-1-ynyl (-C≡CCH ₃ ), prop-2-ynyl (-CH ₂ C≡CH).

The term "cycloalkyl" refers to a fully saturated carbocyclic ring that exists in the form of a monocyclic, cyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is generally a 3- to 10-membered ring. The term "C ₃ -C ₁₀ cycloalkyl" is understood to mean a saturated monocyclic, cyclic, spirocyclic or bridged ring having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of the cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, spiro[4.5]decyl, and the like. The term "C ₃ -C ₁₀ cycloalkyl" may include "C ₃ -C ₆ cycloalkyl". The term "C ₃ -C ₆ cycloalkyl" may be understood to mean a saturated monocyclic or bicyclic hydrocarbon ring having 3, 4, 5 or 6 carbon atoms. Specific examples include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The term "cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and exists in the form of a monocyclic, fused, bridged or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is generally a 5- to 8-membered ring. Specific examples of the cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl or cycloheptadienyl, etc.

The term "heterocyclyl" refers to a fully saturated or partially saturated (heteroaromatic as a whole that is not aromatic) monocyclic, fused, spiro or bridged ring group, which contains 1, 2, 3, 4 or 5 heteroatoms or heteroatomic groups (i.e., heteroatomic groups containing heteroatoms) in the ring atoms, and the "heteroatoms or heteroatomic groups" include but are not limited to nitrogen atom (N), oxygen atom (O), sulfur atom (S), phosphorus atom (P), boron atom (B), -S(=O) _2- , -S(=O)-, -P(=O) _2- , -P(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH- or -NHC(=O)NH-, etc. The term "3-10 membered heterocyclyl" refers to a heterocyclyl group having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms, and containing 1, 2, 3, 4 or 5 heteroatoms or heteroatomic groups independently selected from the above-mentioned in the ring atoms. “3-10 membered heterocyclic group” includes “4-7 membered heterocyclic group”, wherein specific examples of 4 membered heterocyclic group include but are not limited to azetidinyl or oxetanyl; specific examples of 5 membered heterocyclic group include but are not limited to tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrooxazolyl or 2,5-dihydro-1H-pyrrolyl; specific examples of 6 membered heterocyclic group include but are not limited to tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridinyl or 4H-[1,3,4]thiadiazinyl; specific examples of 7 membered heterocyclic group include but are not limited to diazepanyl. The heterocyclic group may also be a bicyclic group, wherein specific examples of 5,5-membered bicyclic groups include but are not limited to hexahydrocyclopenta[c]pyrrole-2(1H)-yl; specific examples of 5,6-membered bicyclic groups include but are not limited to hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl or 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl. Optionally, the heterocyclic group may be a benzo-fused ring group of the above 4-7-membered heterocyclic group, specific examples of which include but are not limited to dihydroisoquinolinyl and the like. "4-10 membered heterocyclyl" may include "5-10 membered heterocyclyl", "4-7 membered heterocyclyl", "5-6 membered heterocyclyl", "6-8 membered heterocyclyl", "4-10 membered heterocycloalkyl", "5-10 membered heterocycloalkyl", "4-7 membered heterocycloalkyl", "5-6 membered heterocycloalkyl", "6-8 membered heterocycloalkyl", etc., and "4-7 membered heterocyclyl" may further include "4-6 membered heterocyclyl", "5-6 membered heterocyclyl", "4-7 membered heterocycloalkyl", "4-6 membered heterocycloalkyl", "5-6 membered heterocycloalkyl", etc. Although some bicyclic heterocyclyls in the present disclosure partially contain a benzene ring or a heteroaromatic ring, the heterocyclyl as a whole is still non-aromatic.

The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group with a conjugated π electron system. The aryl group may have 6-20 carbon atoms, 6-14 carbon atoms or 6-12 carbon atoms. The term "C ₆ -C ₂₀ aryl" is understood to mean an aryl group having 6 to 20 carbon atoms. In particular, a ring having 6 carbon atoms ("C ₆ aryl"), such as phenyl; or a ring having 9 carbon atoms The term "C _{6 -C 10} aryl" is understood to mean an aryl group having 6 to 10 carbon atoms. In particular, it is a ring having 6 carbon atoms ("C ₆ aryl"), for example phenyl; or a ring having 9 carbon atoms ("C ₉ aryl"), for example indanyl or indenyl; or a ring having 10 carbon atoms ("C 10 aryl"), for example tetrahydronaphthyl, dihydronaphthyl or naphthyl; or a ring having 13 carbon atoms ("C _{13 aryl"), for example fluorenyl; or a ring having 14 carbon atoms ("C 14} aryl"), for example anthracenyl. The term "C ₆ -C ₁₀ aryl" is understood to mean an aryl group having 6 to 10 carbon atoms. In particular, it is a ring having 6 carbon atoms ("C ₆ aryl"), for example phenyl; or a ring having 9 carbon atoms ("C ₉ aryl"), for example indanyl or indenyl; or a ring having 10 carbon atoms ("C ₁₀ aryl"), for example tetrahydronaphthyl, dihydronaphthyl or naphthyl. The term "C ₆ -C ₂₀ aryl group" may include "C ₆ -C ₁₀ aryl group".

The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system with aromaticity, which contains at least one ring atom selected from N, O, S, and the remaining ring atoms are C. The term "5-10 membered heteroaryl" is understood to include monocyclic or bicyclic aromatic ring systems: which have 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and which contain 1, 2, 3, 4 or 5, preferably 1, 2 or 3 heteroatoms independently selected from N, O and S. In particular, the heteroaryl group is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl, and the like, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl or isoindolyl, and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl or isoquinolyl, and the like; or azinyl, indolizinyl, purinyl, and the like, and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl or phenoxazinyl, and the like. The term "5-6 membered heteroaryl" refers to an aromatic ring system having 5 or 6 ring atoms and which contains 1-3, preferably 1-2 heteroatoms independently selected from N, O and S.

The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "therapeutically effective amount" means an amount of a compound of the present disclosure that (i) treats a particular disease, condition or disorder, (ii) alleviates, ameliorates or eliminates one or more symptoms of a particular disease, condition or disorder, or (iii) delays the onset of one or more symptoms of a particular disease, condition or disorder described herein.

The amount of a compound of the disclosure that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art based on his or her knowledge and this disclosure.

The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to a salt of a pharmaceutically acceptable acid or base, including a salt formed between a compound and an inorganic acid or an organic acid, and a salt formed between a compound and an inorganic base or an organic base.

The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or their salts and a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to an organism.

The term "pharmaceutically acceptable excipients" refers to those excipients that have no significant irritation to the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

The word "comprise" or "comprises" and its English variations such as comprises or comprising are to be construed as having an open, non-exclusive meaning, ie, "including but not limited to".

The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from that normally found in nature. Examples of isotopes that may be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ^{13 N, 15} N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ¹²³ I, ¹²⁵ I, and ³⁶ Cl ^, etc., respectively.

Certain isotopically labeled compounds of the present disclosure (e.g., labeled with ³ H and ¹⁴ C) can be used in compound and/or substrate tissue distribution assays. Tritiated (i.e., ³ H) and carbon-14 (i.e., ¹⁴ C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes, such as ¹⁵ O, ¹³ N, ¹¹ C, and ¹⁸ F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present disclosure can generally be prepared by the following procedures similar to those disclosed in the schemes and/or examples below, by substituting an isotopically labeled reagent for an unlabeled reagent.

The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients, for example, they can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.

Typical routes of administration of the disclosed compounds or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

The pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, emulsification methods, freeze-drying methods, and the like.

In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present disclosure to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.

Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into particles to obtain a tablet or sugar-coated core. Suitable excipients include, but are not limited to, adhesives, diluents, disintegrants, lubricants, glidants or flavoring agents, etc.

The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

In all the administration methods described herein of the compound of formula (I) or the above-mentioned compound or a pharmaceutically acceptable salt thereof, the daily dosage is 0.01 mg/kg to 200 mg/kg body weight, in the form of single or divided doses.

Detailed ways

The invention is described in detail below by way of examples, but this does not imply any adverse limitation of the present disclosure. The present disclosure has been described in detail herein, and specific embodiments thereof are disclosed therein, and it will be apparent to those skilled in the art that various changes and modifications may be made to the specific embodiments of the present disclosure without departing from the spirit and scope of the present disclosure. All reagents used in the present disclosure are commercially available and can be used without further purification.

Unless otherwise specified, the ratio of mixed solvents is the volume ratio. For example, "the eluent is 10%-75% acetonitrile-water" means that the volume ratio of acetonitrile to water in the gradient elution process is 10:90-75:25.

Unless otherwise stated, % refers to wt %.

Compounds are manually or The software names were used, and commercially available compounds were named using the supplier's catalog names.

The structure of the compound is determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). The unit of NMR shift is 10 ^-6 (ppm). The solvent for NMR measurement is deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS); "IC ₅₀ " refers to the half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved.

Abbreviations:

THF: tetrahydrofuran; Ti(OEt) ₄ : tetraethyl titanate; Toluene: toluene; n-BuLi: n-butyl lithium; EA: ethyl acetate; DCM: dichloromethane; DIEA: N,N-diisopropylethylamine; Boc ₂ O: di-tert-butyl dicarbonate; m-CPBA: m-chloroperbenzoic acid; DMF: N,N-dimethylformamide; dioxane: dioxane; CDI: N,N'-carbonyldiimidazole; XPhos Pd G2: chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II); MeI: iodomethane; Cs ₂ CO ₃ : cesium carbonate; 2-iodo-propane: 2-iodopropane; LiAlH ₄ : lithium aluminum hydride; Acetone: acetone; EtOH: anhydrous ethanol; TEA or Et ₃ N: triethylamine; CD ₃ I: deuterated iodomethane; Pd(OAc) ₂ : palladium acetate; PPh ₃ : triphenylphosphine; Pd(OH) ₂ : palladium hydroxide; SOCl ₂ : thionyl chloride; HFIP: hexafluoroisopropanol; KF: potassium fluoride; MeCN or CH ₃ CN: acetonitrile; MeMgBr: methylmagnesium bromide; Pd ₂ (dba) ₃ : tris(bisbenzylideneacetone)bispalladium; PCy ₃ : tricyclohexylphosphine; TsOH: p-toluenesulfonic acid; CH ₂ O: formaldehyde.

Example 1: 7'-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1'-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1'H-spiro[cyclobutane-1,4'-pyrimido[4,5-d]pyrimidin]-2'(3'H)-one (Compound 1)

Step 1: Synthesis of Intermediate 1C

Cyclobutanone 1A (10.0 g, 142.0 mmol) and intermediate 1B (15.7 g, 130 mmol) were dissolved in tetrahydrofuran (100 mL), and tetraethyl titanate (88.8 g, 389.0 mmol) was added to react at 50°C for 5 hours. Ice water (100 mL) and ethyl acetate (100 mL) were added to the reaction solution, and then saturated sodium bicarbonate aqueous solution (20.0 mL) was added and stirred for 1 hour. The resulting mixture was filtered, the filter cake was washed with ethyl acetate, the filtrate was dried over anhydrous sodium sulfate, filtered, concentrated to obtain a crude product, and then purified by silica gel column (eluent: petroleum ether: ethyl acetate = 10:1-3:1) to obtain intermediate 1C (13 g, yield 58%).

Step 2: Synthesis of Intermediate 1E

Compound 1D (1.5 g, 6.4 mmol) was dissolved in toluene (12.0 mL), replaced with nitrogen 3 times, and n-butyl lithium (1.6 M, 4.7 mL) was added dropwise at -78 ° C. The reaction was continued for 5 min at -78 ° C. Then, intermediate 1C (1.0 g, 5.8 mmol) was dissolved in toluene (12.0 mL) and added dropwise to the above reaction solution. The reaction was stirred at -78 ° C for 30 min. The reaction solution was directly concentrated, and the obtained crude product was purified by silica gel column (eluent: dichloromethane: methanol = 100: 1-10: 1) to obtain intermediate 1E (0.9 g, yield 47%). m/z (ESI): 334.1 [M + H] ⁺ .

Step 3: Synthesis of Intermediate 1F

Intermediate 1E (300 mg, 898 μmol) was dissolved in hydrochloric acid-ethyl acetate (2.0 mol/L, 3.0 mL) and reacted at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate (10 mL), then extracted with water (20 mL), and the separated aqueous phase was adjusted to pH = 9 with saturated sodium carbonate solution, and then extracted with ethyl acetate (15 mL*3). The obtained organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound 1F (300 mg, crude product), which can be directly used in the next step.

Step 4: Synthesis of Intermediate 1G

Add the intermediate 1F (300.0 mg, about 0.90 mmol) prepared in the previous step and dissolve it in dichloromethane (3.0 mL), then add N,N-diisopropylethylamine (422.0 mg, 568.0 μL) and di-tert-butyl dicarbonate (570.0 mg, 600.0 μL). The resulting mixture was stirred at room temperature for 2 hours. The reaction solution was directly concentrated, and the residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 100: 1-10: 1) to obtain intermediate 1G (280 mg, yield 94%). m/z (ESI): 330.1 [M + H] ⁺ .

Step 5: Synthesis of Intermediate 1H

Dissolve intermediate 1G (280.0 mg, 0.85 mmol) in dichloromethane (3.0 mL), add m-chloroperbenzoic acid (465.0 mg, 2.3 mmol). The resulting mixture was stirred at room temperature for 3 hours. Dichloromethane (10 mL) was added to the reaction solution to dilute it, and then washed with saturated sodium thiosulfate aqueous solution (5.0 mL). The organic phase was separated and washed with saturated sodium bicarbonate aqueous solution (10.0 mL) and concentrated. The residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 10:1-3:1) to obtain intermediate 1H (190 mg, yield 62%). m/z (ESI): 362.1 [M + H] ⁺ .

Step 6: Synthesis of Intermediate 1J

Compound 1I (106.0 mg, 414.0 μmol) was dissolved in N,N-dimethylformamide (1.0 mL), and N,N-diisopropylethylamine (161.0 mg, 1.2 mmol) was added, and then intermediate 1H (150.0 mg, 414.0 μmol) was added, and the resulting mixture was stirred at room temperature for 3 hours. After the reaction solution was concentrated, the residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 10:1-2:1) to obtain intermediate 1J (100 mg, yield 45%). m/z (ESI): 537.1 [M + H] ⁺ .

Step 7: Synthesis of Intermediate 1K

Intermediate 1J (80.0 mg, 149.0 μmol) was dissolved in hydrochloric acid-dioxane (1.0 mL) and reacted at room temperature for 1 hour. The reaction solution was directly concentrated to obtain intermediate 1K (80 mg, crude product) which was directly used in the next step.

Step 8: Synthesis of Intermediate 1L

The intermediate 1K (50.0 mg, 114.5 μmol) was dissolved in dichloromethane (3.0 mL), and N,N-diisopropylethylamine (68.3 mg, 528.0 μmol) and N,N'-carbonyldiimidazole (45.6 mg, 281.5 μmol) were added, and the resulting mixture was reacted at room temperature for 1 hour. After the reaction solution was concentrated, the residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 10:1-3:1) to obtain the intermediate 1L (40 mg, yield 82%). m/z (ESI): 463.0 [M + H] ⁺ .

Step 9: Synthesis of 7'-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1'-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1'H-spiro[cyclobutane-1,4'-pyrimido[4,5-d]pyrimidin]-2'(3'H)-one (Compound 1)

The intermediate 1L (40.0 mg, 86.4 μmol), (4-cyclopropyl-6-methoxy-pyrimidin-5-yl)boric acid (36.8 mg, 190.0 μmol), potassium phosphate (55.0 mg, 259.0 μmol), chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium (II) (27.2 mg, 34.6 μmol) were added to a mixed solution of dioxane (1.0 mL) and water (50 uL). The resulting reaction solution was stirred at 100 ° C under nitrogen protection for 4 hours. The reaction solution was concentrated and the residue was purified by preparative chromatography (Waters Xbridge C ₁₈ 150*19 mm, 10 μm, eluent 10%-75% acetonitrile-water) to obtain the title compound 1 (14 mg, yield 28%).

LC-MS: m/z(ESI):577.1[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.80 (s, 1H), 8.66 (s, 1H), 7.55-7.48 (m, 4H), 7.29 (s, 1H), 5.80 (s, 1H), 5.32 (s, 2H), 3.92 (s, 3H), 3.73 (s, 3H), 2.76-2.64 (m, 2H), 2.62-2.46 (m, 2H), 2.13-2.01 (m, 2H), 1.71-1.68 (m, 1H), 1.24-1.19 (m, 2H), 0.87-0.82 (m, 2H).

Example 2: 7'-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-3'-methyl-1'-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1'H-spiro[cyclobutane-1,4'-pyrimido[4,5-d]pyrimidin]-2'(3'H)-one (Compound 2)

Compound 1 (10.0 mg, 17.3 μmol) was dissolved in N,N-dimethylformamide (0.5 mL), and cesium carbonate (16.9 mg, 52.0 μmol) and iodomethane (4.9 mg, 34.7 μmol) were added. The resulting mixture was stirred at room temperature for 2 h. 0.5 mL of water was added to the reaction solution, and the resulting solution was directly purified by preparative chromatography (Waters Xbridge C ₁₈ 150*19 mm, 10 μm, eluent 10%-75% acetonitrile-water) to obtain the title compound 2 (2.3 mg, yield 22%).

LC-MS: m/z(ESI):591.2[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.81 (s, 1H), 8.66 (s, 1H), 7.55-7.46 (m, 4H), 7.29 (s, 1H), 5.34 (s, 2H), 3.93 (s, 3H), 3.73 (s, 3H), 3.26 (s, 3H), 3.04-2.93 (m, 2H), 2.52-2.41 (m, 2H), 2.13-2.04 (m, 2H), 1.71-1.69 (m, 1H), 1.23-1.17 (m, 2H), 0.89-0.84 (m, 2H).

Example 3

Using a route and synthesis method similar to steps 2 to 9 in Example 1, replacing intermediate 1C in step 2 with compound A in the following table, the corresponding compounds 3-5 in the table were prepared.

Example 4

Using a route and synthesis method similar to steps 2 to 9 of Example 1, the intermediate 1C in step 2 was replaced by compound B in the following table, and 1I in step 6 was replaced by compound C in the following table to prepare the corresponding compounds 6 and 7 in the table.

Example 5

Using a similar synthesis method as in Example 2, compound 1 was replaced with compounds 3, 4, 6, and 7, respectively, to prepare the corresponding compounds 8-11 in the table.

Example 6: 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5-methyl-5,8-dihydropteridine-6,7-dione (Compound 12)

Step 1: Synthesis of intermediate 12B

At room temperature, intermediate 12A (8.8 g, 37.0 mmol), 2-iodopropane (12.6 g, 74.0 mmol), potassium carbonate (10.2 g, 74.0 mmol) and N,N-dimethylformamide (100 mL) were added to the reaction flask, and the resulting mixture was stirred at 60°C for 2 hours. The reaction solution was poured into 200 mL of ice water and extracted with 100 mL of ethyl acetate three times. The organic phases were combined, washed with saturated brine and concentrated, and the resulting residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 10:1-1:1) to obtain intermediate 12B (3.4 g, yield: 33%). m/z (ESI): 280.1 [M + H] ⁺ .

Step 2: Synthesis of intermediate 12C

At room temperature, the intermediate 12B (3.4 g, 12.2 mmol) was dissolved in tetrahydrofuran (30 mL), and lithium aluminum hydride (924.1 mg, 24.4 mmol) was added in batches at 0°C. The resulting mixture was stirred at 0°C for 1 hour and then slowly returned to room temperature and continued to stir for 1 hour. After the reaction solution was cooled to 0°C, 0.1 mL of water, 0.1 mL of 15% sodium hydroxide aqueous solution and 0.2 mL of water were added in sequence. The resulting mixture was stirred at room temperature for 1 hour and then filtered through diatomaceous earth, and the filter cake was rinsed with dichloromethane. The filtrate was concentrated to obtain the intermediate 12C (3.4 g, yield: 100%), which was used directly in the next step. m/z (ESI): 284.1 [M + H] ⁺ .

Step 3: Synthesis of intermediate 12E

At room temperature, 2,4-dichloro-5-nitropyrimidine (1.2 g, 6.0 mmol) was dissolved in tetrahydrofuran (30 mL), and N,N-diisopropylethylamine (1.6 g, 12.0 mmol) was added. After the reaction solution was cooled to 0°C, the intermediate 12C (1.7 g, 6.0 mmol, 1 eq.) was added under stirring. The resulting mixture was stirred at 0°C for 0.5 hours and then slowly returned to room temperature, and the reaction was continued for 2 hours. The resulting reaction solution was concentrated to obtain a crude product, which was then purified by silica gel column (eluent: petroleum ether: ethyl acetate = 5:1-1:1) to obtain the intermediate 12E (1.4 g, yield: 52%). m/z (ESI): 441.1 [M+H] ⁺ .

Step 4: Synthesis of intermediate 12F

At room temperature, reduced iron powder (1.8 g, 31.8 mmol) was added to water (10 mL) and ethanol (30 mL), ammonium chloride (1.7 g, 31.8 mmol) was added, and then intermediate 12E (1.4 g, 3.2 mmol) was added. After the resulting mixture was reacted at 80 ° C for 2 hours, 100 mL of ethyl acetate was added to dilute it. The mixture was filtered, the filter cake was rinsed with ethyl acetate, the filtrate was combined, washed with saturated brine, and concentrated to obtain a crude intermediate 12F (1.4 g, yield: 100%), which was directly used in the next step. m/z (ESI): 411.1 [M + H] ⁺ .

Step 5: Synthesis of intermediate 12H

At room temperature, 12F (1.2 g, 2.9 mmol) was added to acetone (20 mL), followed by potassium carbonate (806.2 mg, 5.8 mmol). The reaction solution was cooled to 0°C, ethyl 2-chloro-2-oxoacetate (398.8 mg, 2.9 mmol) was slowly added under stirring, and the reaction was continued at this temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 2:1-1:1) to obtain intermediate 12H (1.2 g, yield: 80%). m/z (ESI): 511.1 [M+H] ⁺ .

Step 6: Synthesis of intermediate 12I

Intermediate 12H (1.2 g, 2.4 mmol) was added to anhydrous ethanol (10 mL), followed by triethylamine (474.5 mg, 4.7 mmol). The resulting mixture was heated and stirred at 120°C for 2 hours and then concentrated. The resulting residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 2:1-1:1) to obtain intermediate 12I (600 mg, yield: 55%). m/z (ESI): 465.1 [M+H] ⁺ .

Step 7: Synthesis of Intermediate 12J

The intermediate 12I (100.0 mg, 215.1 μmol) was added to anhydrous N,N-dimethylformamide (2 mL), followed by potassium carbonate (59.4 mg, 430.3 μmol) and iodomethane (61.1 mg, 430.3 μmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction solution was added to 20 mL of water and extracted with ethyl acetate three times (20 mL*3). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 2:1-1:1) to obtain the intermediate 12J (100 mg, yield: 97%). m/z (ESI): 479.1 [M+H] ⁺ .

Step 8: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5-methyl-5,8-dihydropteroidine-6,7-dione (Compound 12)

Intermediate 12J (100.0 mg, 208.8 μmol), (4-cyclopropyl-6-methoxy-pyrimidin-5-yl)boronic acid (83.5 mg, 430.3 μmol), potassium phosphate (91.2 mg, 430.3 μmol), XPhos Pd G2 (33.9 mg, 43.0 μmol) were added to dioxane (4 mL) and water (0.4 mL), and the resulting mixture was stirred at 100 ° C for 4 hours under nitrogen protection. After the reaction solution was concentrated, 3 mL of acetonitrile was added and the solid was removed by filtration. The filtrate was purified by preparative chromatography (Waters Xbridge C ₁₈ 150*19 mm, 10 μm, eluent 10%-75% acetonitrile-water) to obtain the title compound 12 (50 mg, yield: 39%).

LC-MS: m/z(ESI):593.2[M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.96 (s, 1H), 8.67 (s, 1H), 8.18 (s, J = 1.4 Hz, 1H), 7.54–7.42 (m, 4H), 5.45 (s, 2H), 4.40 (d, J = 6.6 Hz, 1H), 3.81 (s, 3H), 3.61 (s, 3H), 1.70–1.61 (m, 1H), 1.38 (d, J = 6.7 Hz, 6H), 1.03–0.95 (m, 2H), 0.77–0.68 (m, 2H).

Example 7: 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-methyl-8-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-5,8-dihydropteridine-6,7-dione (Compound 13)

Using a similar route and synthetic method to steps 3 to 8 in Example 6, intermediate 6I was used to replace intermediate 12C in step 3 to prepare compound 13.

MS m/z(ESI):565.2[M+H] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.95(s,1H),8.67(s,1H),7.61–7.41(m,4H),6.75(s,1H),5.44(s,2H),3.80(s,3H),3.60(s,3H),2.30(s,3H),1.72–1.57(m, 1H), 1.06–0.94 (m, 2H), 0.83–0.65 (m, 2H).

Example 8: 2-(4-cyclopropyl-6-difluoromethoxypyrimidin-5-yl)-5-methyl-8-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-5,8-dihydropteridine-6,7-dione (Compound 14)

Using a route and synthetic method similar to steps 3 to 8 in Example 6, intermediate 6I was used to replace intermediate 12C in step 3, and intermediate 14M was used to replace (4-cyclopropyl-6-methoxy-pyrimidin-5-yl)boronic acid in step 8 to prepare compound 14.

MS m/z(ESI):601.2[M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.02 (s, 1H), 8.80 (s, 1H), 8.01–7.63 (m, 2H), 7.63–7.59 (m, 2H), 7.50 (m, 2H), 5.45 (s, 2H), 3.74 (s, 3H), 3.62 (s, 3H), 1.78 (m, 1H), 1.06 (m, 2H), 0.82 (m, 2H).

Example 9: 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-(methyl-d3)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,8-dihydropteridin-6(5H)-one (Compound 15)

Step 1: Synthesis of 2-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5-nitropyrimidin-4-amine (15A)

At room temperature, 2,4-dichloro-5-nitropyrimidine (0.71 g, 3.7 mmol) and N,N-diisopropylethylamine (1.0 g, 7.8 mmol, 2.0 eq) were dissolved in tetrahydrofuran (20 mL). After cooling to 0°C, 1I (0.93 g, 3.7 mmol, 1.0 eq) was added to the reaction solution. The resulting mixture was stirred at 0°C for 0.5 hours and then slowly returned to room temperature for 2 hours. The reaction solution was added to ice water (50 mL) and extracted with ethyl acetate (50 mL*3). The organic phases were combined and washed once with saturated brine (50 mL). After the solvent was removed by distillation under reduced pressure, the resulting residue was purified by silica gel column (petroleum ether: ethyl acetate = 5:1-3:1) to obtain a yellow solid 15A (0.90 g, yield 60%). m/z (ESI): 413 [M+H] ⁺ .

Step 2: Synthesis of 2-chloro-N ⁴ -(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidine-4,5-diamine (15B)

At room temperature, compound 15A (0.5 g, 1.2 mmol) and reduced iron powder (0.68 g, 12 mmol, 10 eq) were added to water (5 mL) and ethanol (5 mL), and then ammonium chloride (0.65 g, 12 mmol, 10 eq) was added. The resulting mixture was stirred at 80 ° C for 2 hours. 50 mL of ethyl acetate was added to the reaction solution for dilution and filtered while hot. The filter cake was rinsed with ethyl acetate. After the organic phase was distilled under reduced pressure to remove the solvent, the resulting residue was purified by silica gel column (petroleum ether: ethyl acetate = 1:1) to obtain a yellow-brown solid 15B (0.35 g, yield 76%). m/z (ESI): 383 [M+H] ⁺ .

Step 3: Synthesis of 2-chloro-N-(2-chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)pyrimidin-5-yl)acetamide (15D)

At room temperature, 15B (0.5 g, 1.3 mmol) was dissolved in anhydrous N, N-dimethylformamide (10 mL). After the resulting solution was cooled to 0°C, chloroacetyl chloride (0.15 g, 1.3 mmol, 1 eq) was slowly added, followed by potassium carbonate (0.36 g, 2.61 mmol, 2 eq). After the resulting mixture was reacted at 0°C for 2 hours, water (30 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (20 mL*3). The resulting organic phases were combined, washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. After the organic phase was distilled under reduced pressure to remove the solvent, the resulting residue was purified by silica gel column (petroleum ether: ethyl acetate = 5:1-1:1) to obtain a white solid 15D (0.4 g, yield 67%). m/z (ESI): 459 [M+H] ⁺ .

Step 4: Synthesis of 2-chloro-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,8-dihydropteridin-6(5H)-one (15E)

At room temperature, 15D (0.3 g, 0.65 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL), and potassium carbonate (0.18 g, 1.3 mmol, 2 eq) was added. The resulting mixture was heated to 50°C and stirred for 2 hours, then quenched with water (30 mL), and extracted with ethyl acetate (20 mL*3). The resulting organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. After the organic phase was distilled under reduced pressure to remove the solvent, the resulting residue was purified by silica gel column (petroleum ether: ethyl acetate = 5:1-1:1) to obtain a white solid 15E (0.12 g, yield 44%). m/z (ESI): 423 [M+H] ⁺ .

Step 5: Synthesis of 2-chloro-5-(methyl-d3)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,8-dihydropteridin-6(5H)-one (15F)

Intermediate 15E (200.0 mg, 473.1 μmol) was added to N,N-dimethylformamide (2 mL), and cesium carbonate (308.3 mg, 946.1 μmol) was added. The reaction solution was cooled to 0°C, and deuterated iodomethane (82.3 mg, 567.7 μmol) was slowly added under stirring, and the reaction was carried out at 0°C for 2 hours. The obtained reaction solution was concentrated and the obtained residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 1:1-1:4) to obtain intermediate 15F (160.0 mg, 363.8 μmol, yield 77%). m/z (ESI): 440.8 [M + H] ⁺ .

Step 6: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-(methyl-d3)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,8-dihydropteridin-6(5H)-one (Compound 15)

Intermediate 15F (50.0 mg, 113.7 μmol), (4-cyclopropyl-6-methoxy-pyrimidin-5-yl)boric acid (39.7 mg, 204.6 μmol), potassium phosphate (72.4 mg, 341.0 μmol), XPhos Pd G2 (17.8 mg, 22.7 μmol) were added to 1,4-dioxane (2 mL) and water (0.4 mL). The resulting mixture was stirred at 100 ° C for 4 hours under nitrogen protection. After the reaction solution was concentrated, 3 mL of acetonitrile was added to the reaction solution and the solid was removed by filtration. The filtrate was purified by preparative chromatography (Waters Xbridge C ₁₈ 150*19mm, 10 μm, eluent was 10%-75% acetonitrile-water) to obtain compound 15 (25.0 mg, 45.2 μmol, yield 40%).

LC-MS: m/z(ESI):554.2[M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.62 (s, 1H), 8.14 (s, 1H), 7.93 (s, 1H), 7.67 (d, J=8.0 Hz, 2H), 7.48 (d, J=8.0 Hz, 2H), 4.83 (s, 2H), 4.23 (s, 2H), 3.86 (s, 3H), 3.76 (s, 3H), 1.76-1.83 (m, 1H), 0.99-1.02 (m, 2H), 0.82-0.86 (m, 2H).

Example 10: 2-(4-cyclopropyl-6-difluoromethoxypyrimidin-5-yl)-5-(methyl-d3)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,8-dihydropteridin-6(5H)-one (Compound 16)

A similar synthesis method to step 6 in Example 9 was used to prepare compound 16 by replacing (4-cyclopropyl-6-methoxy-pyrimidin-5-yl)boronic acid with intermediate 14M.

LC-MS: m/z(ESI):590.2[M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.74 (s, 1H), 8.18 (s, 1H), 7.92 (s, 1H), 7.74 (t, J=62.7 Hz, 1H), 7.65 (d, J=8.0 Hz, 2H), 7.49 (d, J=8.3 Hz, 2H), 4.85 (s, 2H), 4.24 (s, 2H), 3.76 (s, 3H), 1.93 (m, 1H), 1.07 (m, 2H), 0.94 (m, 2H).

Embodiment 11

Using a route and synthesis method similar to steps 1 to 6 in Example 9, the intermediate 1I in step 1 was replaced by compound D in the following table, and deuterated iodomethane was replaced by iodomethane to prepare the corresponding compounds 17-19 in the table.

Among them, the synthesis of intermediate 17A:

Step 1: Synthesis of intermediate 17AC

Under nitrogen protection, add intermediate 17AA (2.3 g, 7.2 mmol) to N,N-dimethylformamide (20 mL), then add palladium acetate (161.1 mg, 719.1 μmol), triphenylphosphine (377.2 mg, 1.4 mmol), intermediate 17AB (1.06 g, 10.8 mmol), triethylamine (1.45 g, 14.4 mmol), stir evenly, and react at 100 ° C for 3 hours. Pour the reaction solution into 100 mL of water, extract with ethyl acetate (50 mL*3), combine the obtained organic phases, wash with saturated brine (50 mL), dry and filter with anhydrous sodium sulfate, distill the organic phase under reduced pressure to remove the solvent, and purify the obtained residue with silica gel column (eluent: dichloromethane: methanol = 20: 1-10: 1) to obtain intermediate 17AC (1.5 g, yield: 72%). m/z (ESI): 320.1 [M + H] ⁺ .

Step 2: Synthesis of intermediate 17AD

Under nitrogen protection, intermediate 17AC (1.54 g, 4.9 mmol) was added to ethanol (20 mL), and palladium hydroxide (150.0 mg) and palladium carbon (150.0 mg) were added, stirred evenly, replaced with hydrogen three times, and stirred at room temperature for 3 hours under hydrogen atmosphere. The reaction liquid was filtered and the filtrate was concentrated to obtain the crude intermediate 17AD (1.1 g, yield: 65%), which was directly used for the next step reaction. m/z (ESI): 324.1 [M + H] ⁺ .

Step 3: Synthesis of intermediate 17AE

Add intermediate 17AD (500.0 mg, 1.5 mmol) to chloroform (20 mL), cool to 0°C in an ice-water bath, slowly add thionyl chloride (184.0 mg, 1.5 mmol), then return to room temperature and stir for 3 hours. Concentrate the reaction solution, and purify the residue with a silica gel column (eluent: dichloromethane: methanol = 20:1) to obtain intermediate 17AE (300 mg, yield: 60%). m/z (ESI): 342.1 [M + H] ⁺ .

Step 4: Synthesis of intermediate 17AF

The intermediate 17AE (300.0 mg, 876.0 μmol) was added to N,N-dimethylformamide (10 mL), and then cesium carbonate (570.0 mg, 1.7 mmol) was added, and the temperature was raised to 100°C, and the reaction was stirred for 1 hour. The reaction solution was concentrated, and the residue was purified by silica gel column (eluent: dichloromethane: methanol = 20:1) to obtain the intermediate 17AF (100 mg, yield: 37%). m/z (ESI): 306.1 [M + H] ⁺ .

Step 5: Synthesis of Intermediate 17A

Intermediate 17AF (100.0 mg, 327 μmol) was added to tetrahydrofuran (5.0 mL), and lithium aluminum hydride (62.9 mg, 1.7 mmol) was slowly added in batches under stirring. The mixture was reacted at room temperature for 2 hours. 1.0 g of sodium sulfate decahydrate was added to the reaction solution, and stirred at room temperature overnight. The reaction solution was diluted with 10 mL of ethyl acetate and filtered, and the filtrate was concentrated to obtain a crude intermediate 17A (100 mg) which was directly used in the next step. m/z (ESI): 310.1 [M+H] ⁺ .

Synthesis of intermediate 18A:

Step 1: Synthesis of intermediate 18AC

The intermediate 18AA (3.6 g, 20 mmol) was added to 20 mL of hexafluoroisopropanol, and triethylamine (5.1 g, 50.5 mmol) and the intermediate 18AB (2.5 g, 20 mmol) were added. The resulting mixture was heated to 70°C and stirred for 1 hour. The reaction solution was concentrated, and 50 mL of water was added, and extracted with ethyl acetate (30 mL*3). The organic phases were combined and concentrated under reduced pressure. The resulting residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 5:1-1:2) to obtain the target intermediate 18AC (3.4 g, yield 75.9%). m/z(ESI):224.1[M+H] ⁺ .

Step 2: Synthesis of intermediate 18A

Intermediate 18AC (2.0 g, 8.9 mmol) was added to tetrahydrofuran (20 mL), and then lithium aluminum hydride (667 mg, 17.6 mmol) was added at low temperature. The reaction was stirred at room temperature for 2 hours. Water (1.0 mL) was added dropwise at 0°C, and then water (1.0 mL), 15% sodium hydroxide aqueous solution (1.0 mL), and water (3.0 mL) were added in sequence to quench the excess lithium aluminum hydride. After filtering with diatomaceous earth, the filter cake was rinsed with dichloromethane, and the organic phase was combined and dried. The residue obtained after the filtrate was concentrated was purified by reverse phase C18 silica gel column (eluent: 5-50% acetonitrile aqueous solution) to obtain intermediate 18A (1.8 g, yield: 88%). m/z (ESI): 228.2 [M+H] ⁺ .

Synthesis of intermediate 19A:

Step 1: Synthesis of intermediate 19AC

Add intermediate 19AA (3.6 g, 20 mmol) to a mixed solvent of 5 mL water and 25 mL tetrahydrofuran, and add sodium bicarbonate (3.5 g, 41.6 mmol). After stirring for 30 minutes, add intermediate 19AB (3.2 g, 20 mmol). After the resulting mixture reacts at room temperature for 30 minutes, it is heated to 70°C and stirred for 30 minutes. The reaction solution is added to 50 mL water, extracted with ethyl acetate (30 mL*3), the organic phases are combined and concentrated under reduced pressure, and the resulting residue is purified by silica gel column (eluent is petroleum ether: ethyl acetate = 5:1-1:2) to obtain the target intermediate 19AC (695 mg, yield 16.5%). m/z (ESI): 210.1 [M+H] ⁺ .

Step 2: Synthesis of intermediate 19AE

Add intermediate 19AC (690.5 mg, 3.3 mmol) to acetonitrile (20 mL), followed by potassium fluoride (575.6 mg, 9.9 mmol) and diethyl bromodifluoromethanephosphonate (1.8 g, 6.6 mmol). React overnight at 60 °C. After the reaction, spin dry the solvent, add the reaction solution to water, extract with ethyl acetate (30 mL*3), concentrate and purify the residue on a silica gel column (eluent: petroleum ether: ethyl acetate = 5:1-1:2) to obtain intermediate 19AE (727 mg, yield: 85%). m/z (ESI): 260.2 [M+H] ⁺ .

Step 3: Synthesis of intermediate 19A

Intermediate 19AE (710 mg, 2.7 mmol) was added to tetrahydrofuran (20 mL), followed by lithium aluminum hydride (207.6 mg, 5.5 mmol) at low temperature, and the reaction was stirred at room temperature for 2 hours. Water (1.0 mL) was added dropwise at 0°C, followed by water (1.0 mL), 15% sodium hydroxide aqueous solution (1.0 mL), and water (3.0 mL) to quench the excess lithium aluminum hydride, and then filtered through diatomaceous earth. The filter cake was rinsed with dichloromethane, and the organic phases were combined and dried by spin drying. The filtrate was concentrated and the residue was purified by reverse phase C18 silica gel column (eluent: 5-50% acetonitrile aqueous solution) to obtain intermediate 19A (680 mg, yield: 94%). m/z (ESI): 264.2 [M+H] ⁺ .

Example 12: 7-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4,4-dimethyl-1-(4-(1-(oxetane-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one (Compound 20)

Step 1: Synthesis of ethyl 2-chloro-4-((4-(1-(oxetane-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)pyrimidine-5-carboxylate (20C)

At room temperature, ethyl 2,4-dichloropyrimidine-5-carboxylate (220 mg, 1.0 mmol, 1.0 eq) was dissolved in acetonitrile (10 mL), and then (4-(1-(oxetane-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methylamine 20B (300 mg, 1.0 mmol, 1.0 eq) and triethylamine (200 mg, 2.0 mmol, 2.0 eq) were added in sequence. The resulting mixture was stirred at room temperature for 10 hours. Water (10 mL) was added to the reaction system, and the resulting solution was extracted with ethyl acetate 3 times (10 mL*3). The organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 2:1-1:2) to obtain intermediate 20C (360 mg, yield 75%). m/z(ESI):482.1[M+H] ⁺ .

Step 2: Synthesis of 2-(2-chloro-4-((4-(1-(oxetan-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)pyrimidin-5-yl)propan-2-ol (20D)

The intermediate 20C (0.3 g, 0.62 mmol) was dissolved in tetrahydrofuran (10 mL), and then methylmagnesium bromide (3.0 M, 1.75 mL) was added in batches under ice bath conditions, and the reaction was kept under ice bath conditions overnight. Water (10 mL) was added to quench, and ethyl acetate (10 mL*3) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 2:1-1:2) to obtain the intermediate 20D (285 mg, 0.61 mmol, yield 81%). LC-MS: m/z (ESI): 468.1 [M+H] ⁺ ;

Step 3: Synthesis of 7-chloro-1-(4-(1-(oxetan-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4,4-dimethyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one (20E)

N,N'-Carbonyldiimidazole (0.18g, 1.1mmol) was dissolved in dichloromethane (2.0mL), followed by the addition of diisopropylethylamine (0.16g, 1.2mmol, 0.21mL), and then intermediate 20D (0.18g, 38.5mmol), and the reaction was stirred overnight at room temperature. Ammonium chloride solution (10mL) was added to quench, followed by extraction with dichloromethane (10mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 2:1-1:2) to obtain intermediate 20E (160mg, yield 84%). m/z (ESI): 494.1 [M+H] ⁺ ;

Step 4: Synthesis of 7-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4,4-dimethyl-1-(4-(1-(oxetan-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one (Compound 20)

At room temperature, compound 20E (75 mg, 0.15 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid 1M (62 mg, 0.32 mmol) were dissolved in 1,4-dioxane (3.0 mL), and 0.5 mL of water was added, followed by tris(bisbenzylideneacetone)bispalladium (83 mg, 0.091 mmol, 0.1 eq), tricyclohexylphosphine (51 mg, 0.18 mmol), and potassium carbonate (0.38 g, 2.7 mmol). The resulting mixture was subjected to microwave reaction at 100 °C under nitrogen atmosphere for 30 minutes. The resulting reaction solution was concentrated, the residue was dissolved in 3 mL of acetonitrile and filtered, and the resulting filtrate was purified by preparative chromatography (Waters Xbridge C ₁₈ 150*19 mm, 10 μm, eluent was 10%-75% acetonitrile-water) to obtain compound 20 (13 mg, yield 14%).

LC-MS:MS m/z(ESI):608.2[M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ )δ8.84(s,1H),8.66(s,1H),8.48(m,1H),7.58–7.31(m,4H),5.48 (m, 1H), 5.24 (s, 2H), 4.82 (m, 4H), 3.82 (s, 3H), 1.78 (s, 6H), 1.73 (m, 1H), 1.00 (m, 2H), 0.80 (m, 2H).

Example 13: 7-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4,4-dimethyl-1-(4-(1-(1-methylpyrrolidin-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one (Compound 21)

Using a synthetic route and method similar to steps 1-4 in Example 12, intermediate 21B was used to replace intermediate 20B to prepare compound 21.

LC-MS: m/z(ESI):635.3[M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ )δ8.84(s,1H),8.66(s,1H),8.00(s,1H),7.51(d,J＝8.2Hz,2H),7.43(d, J＝8.1Hz,2H),5.25(s,2H),4.80–4.68(m,1H),3.82(s,3H),3.03–2.94(m,1H),2.89–2.80(m ,1H),2.58–2.54(m,1H),2.46–2.38(m,1H),2.29(s,3H),2.26–2.18(m,1H),1.99–1.90(m,1H),1.79(s ,6H),1.74–1.65(m,1H),1.03–0.96(m,2H),0.82–0.73(m,2H).

Synthesis of intermediate 21B:

Step 1: Synthesis of intermediate 21BC

The intermediate 21BA (2.8 g, 11.7 mmol) was dissolved in N,N-dimethylformamide (20.0 mL), and then the intermediate 21BB (3.0 g, 11.7 mmol) and potassium carbonate (4.9 g, 35.3 mmol) were added and reacted at 80°C for 12 h. Water (60.0 mL) was added to the reaction solution for dilution, and it was extracted with ethyl acetate (30.0 mL*3). After the organic phases were combined and the solvent was removed by distillation under reduced pressure, the obtained residue was purified by silica gel column (dichloromethane: methanol = 20: 1) to obtain the intermediate 21BC (550 mg, yield: 15%). m/z (ESI): 321.2 [M+H] ⁺ .

Step 2: Synthesis of intermediate 21B

Intermediate 21BC (400.0 mg, 1.25 mmol) was dissolved in tetrahydrofuran (4.0 mL), and lithium aluminum hydride (105.0 mg, 2.8 mmol) was added in batches at -20°C, and the mixture was reacted at room temperature for 20 min. Water (1.0 mL) was added dropwise at 0°C, and then water (1.0 mL), 15% sodium hydroxide (1.0 mL), and water (3.0 mL) were added in sequence to quench the excess lithium aluminum hydride. The reaction solution was filtered, and the residue obtained after the filtrate was concentrated was purified by reverse phase C18 silica gel column (eluent: 5-50% acetonitrile aqueous solution) to obtain intermediate 21B (200 mg, yield: 50%). m/z (ESI): 325.3 [M+H] ⁺ .

Example 14: 7-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4,4-dimethyl-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazine (Compound 22)

Using a synthetic route and method similar to steps 1-2 in Example 12, intermediate 22A was prepared by replacing intermediate 20B with intermediate 1I in step 1. Then, using a synthetic method similar to step 4 in Example 12, intermediate 22A was replaced with intermediate 20E to prepare intermediate 22B.

Intermediate 22B (80.0 mg, 0.15 mmol) and p-toluenesulfonic acid (7.7 mg, 0.044 mmol) were added to toluene (0.5 mL) and aqueous formaldehyde solution (0.5 mL). The resulting mixture was reacted at 110°C for 0.5 hours, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by preparative chromatography (Waters Xbridge C ₁₈ 150*19 mm, 10 μm, eluent 10%-75% acetonitrile-water) to obtain the title compound 22 (20 mg, yield: 24%).

LC-MS: m/z(ESI):552.2[M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ8.60 (s, 1H), 8.31 (s, 1H), 7.92 (s, 1H), 7.69–7.65 (m, 2H), 7.41 (d, J=8.2 Hz, 2H), 4.98 (s, 2H), 4.83 (s, 2H), 3.83 (s, 3H), 3.76 (s, 3H), 1.72 (m, 1H), 1.57 (s, 6H), 0.97 (m, 2H), 0.81 (m, 2H).

Example 15: 2-(4-cyclopropyl-6-difluoromethoxypyrimidin-5-yl)-5-methyl-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,8-dihydropteridin-6(5H)-one (Compound 23)

Using a synthetic method similar to steps 5-6 in Example 9, substituting deuterated iodomethane in step 5 with iodomethane and replacing (4-cyclopropyl-6-methoxy-pyrimidin-5-yl)boronic acid with intermediate 14M, the title compound 23 was prepared.

LC-MS: m/z(ESI):587.1[M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.74 (s, 1H), 8.19 (s, 1H), 7.93 (m, 1H), 7.82 (s, 1H), 7.64 (m, 2H), 7.52–7.47 (m, 2H), 4.85 (s, 2H), 4.24 (s, 2H), 3.76 (s, 3H), 3.31 (s, 3H), 1.93 (m, 1H), 1.07 (m, 2H), 0.93 (m, 2H).

Test Example 1: USP1 enzyme in vitro activity detection experiment

laboratory apparatus:

Experimental Materials:

The USP1 enzyme (Recombinant human his6-USP1/His6-UAF1 Complex Protein, CF) used in the experiment was purchased from R&D, catalog number E-568-050. Store at -80℃ after aliquoting.

The detection kit (Ub-CHOP2-Reporter Deubiquitination Assay Kit) was purchased from Lifesensors, with the catalog number PR1101. It was stored at -80°C after aliquoting. The kit contains a ubiquitinated reporter enzyme, which becomes active after being deubiquitinated by USP1/UAF1. After catalyzing the substrate, the substrate is excited by a 485nm laser to generate an emission light signal of 531nm.

The information of other reagents and consumables required for the experiment is as follows:

experimental method:

The test compound was dissolved in DMSO to 10 mM. The compound and pure DMSO were added to each well of a 384-well plate using a compound dilution and sample pipetting instrument. The highest concentration started from 3 μM, and the sample was diluted 3 times for a total of 8 concentration points. 50 nL of the test compound or DMSO (as a control) was added to each well. The instrument used different ratios to obtain the gradient dilution sample concentration. The enzyme was diluted with a freshly prepared reaction solution (20 mM Tris-HCl (pH 8.0), 2 mM CaCl ₂ , 2 mM β-mercaptoethanol, 0.05% CHAPS (CHAPS was diluted with ddH ₂ O)). 5 μL of the diluted enzyme reaction solution was added to each well, and the enzyme and compound were mixed by centrifugation and shaken, and then centrifuged and placed on ice. The reporter system and substrate of the kit were diluted with the reaction solution, and 5 μL of the diluted liquid was added to each well and centrifuged to mix. Incubate at room temperature for 0.5 hours. The fluorescence signal in each well was measured using an Envision plate reader (PerkinElmer) with an excitation wavelength of 485 nm and an emission wavelength of 530 nm. The _IC50 values of the inhibitory activity of the compounds on enzyme activity were calculated using the four-parameter Logistic Model method.

In the following formula, x represents the logarithmic form of the compound concentration; F(x) represents the effect value (the inhibition rate of enzyme activity under the condition of this concentration): F(x) = (A + ((BA) / (1 + ((C / x) ^ D)))). A, B, C and D are four parameters. The _IC50 value is further calculated using Xlfit as the compound concentration required for 50% enzyme activity inhibition in the best fitting curve.

The test results are shown in Table 1.

Table 1 In vitro inhibitory activity of USP1 enzyme

Test Example 2: USP1 inhibitor inhibition experiment on MDA-MB-436 cell proliferation:

laboratory apparatus:

Experimental Materials:

The cells used in the experiment, MDA-MB-436, were purchased from Kebai Biotechnology Co., Ltd., with the catalog number CBP60385. The cells were subcultured with DMEM medium (containing 10% FBS), and frozen in liquid nitrogen when the cell generation number was low. The cells used in the experiment did not exceed 15 generations.

Detection kit ( Luminescent Cell Viability Assay was purchased from Promega under the catalog number G7573. Store at -30°C after aliquoting. The kit is a homogenous assay for detecting the number of viable cells in culture by quantitatively measuring ATP. The luminescent signal produced by the kit is proportional to the amount of ATP present, which is directly proportional to the number of cells in the culture.

The information of other reagents and consumables required for the experiment is as follows:

experimental method:

The cultured cells were digested with 0.25% Trypsin-EDTA Solution, collected and centrifuged, and resuspended with culture medium DMEM (containing 10% FBS) to adjust the concentration. The cells were seeded on a 384-well plate (400 cells/20μL/well) and cultured overnight in a cell culture incubator at 37°C and 5% CO _2. The compounds and pure DMSO were added to each well of the 384-well plate using an ECHO instrument. The highest concentration started from 10μM, and the concentration was diluted 4 times, with a total of 8 concentration points. 100nL of the test compound or DMSO (as a control) was added to each well. The instrument obtained the gradient dilution sample concentration through different ratios. 30μL of culture medium was added to each well, and after centrifugation and mixing, it was cultured in a cell culture incubator for 7 days (one column of cells was added with CTG detection on the day of drug addition). After the 7th day, 25μL of CTG detection solution was added to each well, and after centrifugation and mixing, it was placed at room temperature in the dark for 10 minutes. The chemiluminescent signal was measured in each well using Envision plate reader (PerkinElmer, emission wavelength 400-700nm). The chemiluminescent value [RLU] cpd on day 7 was obtained for the drug-added group, and the chemiluminescent value [RLU] cell on day 7 was obtained for the drug-free DMSO-added group. The chemiluminescent value [RLU] background on day 0 was obtained by CTG test on day 0 of the drug-free DMSO-added group in parallel. The inhibition rate (Inhibition rate, %) of the compound on proliferation = [1-([RLU] cpd.–[RLU] background)/([RLU] cell–[RLU] background)] × 100%, and the inhibitory activity GI ₅₀ value of the compound on proliferation was calculated using the four-parameter Logistic Model method. In the following formula, x represents the logarithmic form of the compound concentration; F(x) represents the effect value (the inhibition rate of proliferation under the concentration condition): F(x) = (A+((BA)/(1+((C/x)^D)))). A, B, C and D are four parameters. _GI50 values were further calculated using Xlfit as the compound concentration required for 50% inhibition of proliferation in the best-fit curve.

The inhibitory activity of the disclosed compounds on MDA-MB-436 proliferation was determined by the above test, and the measured GI ₅₀ values are shown in Table 2.

Table 2 Inhibitory activity of the disclosed compounds on MDA-MB-436 cell proliferation

Claims (15)

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
   

   in,

   Selected from the following structures:

   R ^3a , R ^3b , R ⁴ , R ^5a , R ^5b are each independently selected from H, halogen, CN, OH, NH ₂ , -C(O)OR ^x , -C(O)R ^x , -NHC(O)R ^x , -OC ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl or 4-10 membered heterocyclyl, and the NH ₂ , -OC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl or 4-10 membered heterocyclyl is optionally substituted with R ^x ;

   or R ^3a , R ^3b and the carbon atom to which they are attached together form a C ₃ -C ₁₀ cycloalkyl group or a 4-10 membered heterocyclic group, and the C ₃ -C ₁₀ cycloalkyl group or the 4-10 membered heterocyclic group is optionally substituted by R ^x ;

   or R ^5a , R ^5b and the carbon atom to which they are attached together form a C ₃ -C ₁₀ cycloalkyl group or a 4-10 membered heterocyclic group, and the C ₃ -C ₁₀ cycloalkyl group or the 4-10 membered heterocyclic group is optionally substituted by R ^x ;

   Ring A is selected from C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl, and the C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl is optionally substituted by ^Ra ;

   Ring B is selected from C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, C ₄ -C ₁₀ cycloalkenyl or C ₃ -C ₁₀ cycloalkyl, wherein the C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, C ₄ -C ₁₀ cycloalkenyl or C ₃ -C ₁₀ cycloalkyl is optionally substituted with R ^b ;

   Ring C is selected from C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl is optionally substituted by R ^c ;

   Each of ^Ra , ^Rb , and ^Rc is independently selected from halogen, CN, OH, _NH2 , -C(O) ^ORx , -C(O) ^Rx , _C1 - _C6 alkyl, _-OC1 - _C6 alkyl, _C3 - _C10 cycloalkyl, or 4-10 membered heterocyclyl, wherein the _NH2 , _C1 - _C6 alkyl, -OC1- _C6 alkyl, _C3 - _C10 cycloalkyl, or _4-10 membered heterocyclyl is optionally substituted by ^Rx ;

   Alternatively, R ^b , R ^c and the atoms to which they are attached together form a C ₄ -C ₁₀ cycloalkenyl group or a 4-10 membered heterocyclic group, and the C ₄ -C ₁₀ cycloalkenyl group or the 4-10 membered heterocyclic group is optionally substituted by R ^x ;

   R ¹ and R ² are independently selected from H, halogen, CN, OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl or 4-10 membered heterocyclyl, wherein the OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl or 4-10 membered heterocyclyl is optionally substituted by R ^x ;

   Alternatively, R ¹ , R ² and the atoms to which they are attached together form a C ₃ -C ₁₀ cycloalkyl group or a 4-7 membered heterocyclic group, and the C ₃ -C ₁₀ cycloalkyl group or the 4-7 membered heterocyclic group is optionally substituted by R ^x ;

   ^Rx is selected from halogen, CN, OH, _NH2 or _C1 - _C6 alkyl, wherein the OH, _NH2 or _C1 - _C6 alkyl is optionally substituted by _C1 - _C6 alkyl, _C3 - _C10 cycloalkyl or 4-7 membered heterocyclyl;

   The condition is that when Selected from When R ^5a is selected from halogen, CN, OH, NH ₂ , -C(O)OR ^x , -C(O)R ^x , -OC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl or 4-9 membered heterocyclyl, wherein the NH ₂ , -OC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl or 4-9 membered heterocyclyl is optionally substituted by R ^x ;

   Alternatively, R ^5a , R ^5b and the carbon atom to which they are attached form a C ₄ -C ₁₀ cycloalkyl group or a 4-9 membered heterocyclic group, and the C ₄ -C ₁₀ cycloalkyl group or the 4-9 membered heterocyclic group is optionally substituted by R ^x .
2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ^3a , R ^3b , R ⁴ , R ^5a , and R ^5b are independently selected from H, -C(O)OR ^x , -C(O)R ^x , -OC ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, or 4-10 membered heterocyclyl, and the -OC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, or 4-10 membered heterocyclyl is optionally substituted by R ^x ;

   Alternatively, R ^3a , R ^3b , R ⁴ , R ^5a , R ^5b are independently selected from H, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ alkyl or C ₃ -C ₁₀ cycloalkyl, and the C ₁ -C ₆ alkyl or C ₃ -C ₁₀ cycloalkyl is optionally substituted with R ^x .
3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, wherein R ^5a , R ^5b and the carbon atom to which they are connected form a C ₃ -C ₁₀ cycloalkyl group, and the C ₃ -C ₁₀ cycloalkyl group is optionally substituted by R ^x .
4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R ^5a , R ^5b and the carbon atom to which they are connected form a C ₄ -C ₁₀ cycloalkyl group, and the C ₄ -C ₁₀ cycloalkyl group is optionally substituted by R ^x .
5. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein ring A is selected from a 5-10 membered heteroaryl group, and the 5-10 membered heteroaryl group is optionally substituted by ^Ra ;

   Alternatively, Ring A is selected from 5-6 membered heteroaryl, which is optionally substituted with ^Ra .
6. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein ring B is selected from C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl, and the C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl is optionally substituted by R ^b ;

   Alternatively, Ring B is selected from C ₆ -C ₁₀ aryl groups, wherein the C ₆ -C ₁₀ aryl groups are optionally substituted with R ^b .
7. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein ring C is selected from a 5-10 membered heteroaryl or a 4-10 membered heterocyclic group, and the 5-10 membered heteroaryl or the 4-10 membered heterocyclic group is optionally substituted by R ^c ;

   Alternatively, Ring C is selected from 5-6 membered heteroaryl or 4-8 membered heterocyclyl, and the 5-6 membered heteroaryl or 4-8 membered heterocyclyl is optionally substituted by R ^c .
8. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein each of ^Ra , ^Rb , and ^Rc is independently selected from halogen, _C1 - _C6 alkyl, _-OC1 - _C6 alkyl, _C3 - _C10 cycloalkyl, or 4-10 membered heterocyclyl, and the _C1 - _C6 alkyl, _-OC1 - _C6 alkyl, _C3 - _C10 cycloalkyl, or 4-10 membered heterocyclyl is optionally substituted by ^Rx .
9. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R ¹ and R ² are independently selected from H, halogen, C ₁ -C ₆ alkyl or C ₃ -C ₁₀ cycloalkyl, and the C ₁ -C ₆ alkyl or C ₃ -C ₁₀ cycloalkyl is optionally substituted by R ^x .
10. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein ^Rx is selected from halogen, _NH2 or _C1 - _C6 alkyl, and the _NH2 or _C1 - _C6 alkyl is optionally substituted by _C1 - _C6 alkyl, _C3 - _C10 cycloalkyl or 4-7 membered heterocyclyl.
11. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein: Selected from the following structures:
12. A compound selected from the following or a pharmaceutically acceptable salt thereof:
    
    
13. A pharmaceutical composition comprising the compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
14. A method for treating a disease mediated by USP1 in a mammal, comprising administering a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, or the pharmaceutical composition according to claim 13, to a mammal, preferably a human, in need of such treatment.
15. Use of the compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 13, in the preparation of a medicament for preventing or treating a disease mediated by USP1.